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© The Rockefeller University Press, 0021-9525/1999//1337 $5.00
The Journal of Cell Biology, Volume 144, Number 6, , 1999 1337-1348

Regular Articles

Extracellular Matrix Regulates Apoptosis in Mammary Epithelium through a Control on Insulin Signaling



Nadia Farrelly, Yi-Ju Lee, Janine Oliver, Caroline Dive, and Charles H. Streuli

School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Adherent epithelial cells require interactions with the extracellular matrix for their survival, though the mechanism is ill-defined. In long term cultures of primary mammary epithelial cells, a laminin-rich basement membrane (BM) but not collagen I suppresses apoptosis, indicating that adhesion survival signals are specific in their response (Pullan et al. 1996. J. Cell Sci. 109:631–642). We now demonstrate that the signal from BM is mediated by integrins and requires both the {alpha}6 and β1 subunits. In addition, a hormonal signal from insulin or insulin-like growth factors, but not hydrocortisone or prolactin, is necessary to suppress mammary cell apoptosis, indicating that BM and soluble factors cooperate in survival signaling. Insulin induced autophosphorylation of its receptor whether mammary cells were cultured on collagen I or BM substrata. However, both the tyrosine phosphorylation of insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase were enhanced in cells cultured on BM, as was the phosphorylation of the phosphatidylinositol 3-kinase effector, protein kinase B. These results suggest a novel extracellular matrix–dependent restriction point in insulin signaling in mammary epithelial cells. The proximal signal transduction event of insulin receptor phosphorylation is not dependent on extracellular matrix, but the activation of downstream effectors requires adhesion to BM. Since phosphatidylinositol 3-kinase was required for mammary epithelial cell survival, we propose that a possible mechanism for BM-mediated suppression of apoptosis is through its facilitative effects on insulin signaling.

Key Words: extracellular matrix • mammary gland • apoptosis • integrin • insulin

Abbreviations used in this paper: BM, basement membrane; ECM, extracellular matrix; EHS, Engelbreth-Holm-Swarm tumor; IGF, insulin-like growth factor; IRS, insulin receptor substrate; PI 3-kinase, phosphatidylinositol 3-kinase; PKB, protein kinase B.

C.H. Streuli is a Wellcome Senior Fellow in Basic Biomedical Science. C. Dive is a Lister Fellow.


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